HIV/AIDS is a global pandemic with nearly 33 million individuals living with HIV infection worldwide. The objectives of this project are to define the unique epidemiological, clinical, virologic, and immunologic features of HIV infection in developing countries, to determine the viral kinetics associated with sexual transmission, and to characterize the molecular strains of HIV internationally for infectiousness and progression of disease. We previously reported the results of a randomized clinical trial of circumcision to prevent HIV acquisition among 4,996 men in Uganda. The estimated efficacy of circumcision was 51% after 2 years but has risen to nearly 75% three years later. Circumcision also afforded a decrease in acquisition of high-risk- human papillomavirus (HR-HPV) in both HIV negative circumcised men as well as the female partners of circumcised men. HR-HPV incidence was 19.7/100py in the circumcised men and 29.4/100py in the control arm (p = 0.006). The incidence of multiple of HR-HPV infections was also reduced to 6.7/100py in the circumcised men and 14.8/100py in the control arm. HR-HPV incidence was lower in the circumcised men for all genotypes and demographic/behavioral subgroups. Among HIV-positive men who were circumcised, there was a lower prevalence of HR-HPV in the HIV-positive men who were circumcised (55.3%) compared to 71.7% in the control group (p<0.01). Multiple HR-HPV infections were found in 22.4% of the circumcised men and in 42.5% in the control arm with a reduction of 47%. New HR-HPV genotypes were acquired in 42% of the circumcised HIV + men and in 57% in the control arm (26% reduction, p = 0.06). Multiple new HR-HPV genotypes were acquired in 10% of the circumcised men and 25% of the control arm (60%;p = 0.01). In summary, circumcision of both HIV-negative as well as HIV-positive men is associated with a reduction in both the prevalence and incidence of multiple HR-HPV infections. Since male circumcision reduces HIV, HPV and HSV-2 acquisition, we examined the cellular basis for these associations and estimated the immunologic cellular densities in foreskin tissues of men who were circumcised in the trial. CD1A+ dendritic cell densities did not vary by HIV or HSV-2 serologic status. When compared to HIV-/HSV-2- men, CD4+ T-cell densities in the foreskin tissue were similar in the HIV+/HSV-2+ group, significantly decreased in the HIV+/HSV-2 - group and increased in the HIV-/HSV-2+ group. CD8+ densities were higher in the HIV+/HSV-2+ infected group compared to the HIV-/HSV-2- group and the HIV+/HSV-2- group and the HIV-/HSV-2+ group (p <0.005). The increased CD4+ cellular density in the HIV-/HSV-2+ men may help explain why HSV-2 infected men are at increased risk for HIV acquisition. The absence of this increase in the HIV+/HSV-2+ group is likely in part due to the progressive loss of CD4+ in HIV infection. Conversely, co-infection with HIV and HSV-2 appear to synergistically increase the CD8+ T-cell densities and may partially explain the failure of acyclovir in decreasing sexual transmission of HIV in dually infected individuals. Microbial translocation has been previously implicated as a contributing factor to the heightened immune activation observed during HIV-1 disease progression. We examined evidence for microbial translocation and its associated immune markers in a longitudinal study of HIV-1 seroconverters in the Rakai cohort, and were not able to demonstrate evidence for microbial translocation and HIV disease progression. In order to examine whether there was any evidence of immune activation associated with HIV disease progression in these Ugandan infected individuals, we also examined the same individuals for levels of C-reactive protein (CRP). CRP levels were significantly increased in the standard progressors (p <0.001) but were not significantly elevated in the long-term nonprogressors. CRP levels during the first year post-HIV seroconversion in the rapid progressors were also significantly higher than that observed in the long-term nonprogressors as well (p <0.05). CRP levels negatively correlated with lipopolysaccharide levels (p <0.05) and were not associated with endotoxin antibody levels. This study suggested that in Uganda, there is evidence for increased immune activation, which is significantly associated with HIV disease progression but not associated with microbial translocation. Thus, the observed increase in microbial translocation and LPS levels seen in the US studies may be a consequence of advanced HIV disease and progression to AIDS and not necessarily causative of the immune activation as we were unable to demonstrate a direct correlation. We have previously reported that HIV-1 subtype D progresses significantly faster than subtype A or recombinants in Rakai, Uganda. We assessed the rate of CD4+ T-decline per year among 312 HIV seroincidence persons infected with different HIV-1 subtypes. A total of 59.6% had subtype D, 15.7% A, 18.9% recombinant viruses, and 5.8% had multiple subtypes. For all subtypes combined, the overall rate of CD4+ T-cell decline was -34.5 cells/ul/yr. Compared with subtype A the adjusted rate of CD4 cell loss was -73.7 cells/ul/yr (p <0.001) for subtype D, -43.2 cells/ul/yr (p = 0.072) for recombinants and -63.9 cells/ul/yr (p = 0.67) for infections with multiple HIV subtypes. In conclusion, infection with subtype D was associated with significantly faster rate of CD4+ T-cell loss than subtype A, which may explain the more rapid disease progression for subtype D compared with subtype A. We then examined whether there were subtype differences in heterosexual transmission among HIV-discordant couples in Rakai. After adjusting for age, viral load, stage of disease, GUD status, and non-use of condoms, subtype A viruses were associated with a two fold increase in the rate of transmission when compared to subtype D, but no difference in transmissions were observed between recombinant viruses and subtype D. Index-positive partners age <30, viral load in the index-negative partners, GUD and non-use of condoms were also significant determinants of HIV transmission. In conclusion, subtype A viruses have a significantly higher rate of heterosexual transmission than subtype D viruses. To analyze whether efficiency of transmission by subtype has a subsequent geographic distribution effect, we sequenced HIV subtypes for 773 subjects residing in 10 community clusters in rural Uganda from 1994 and in 812 individuals in 2002. Subtype A (16.7%) and D (70.3%) were the most common strains in the population at baseline. The change in subtype distribution of the population as a whole in the quartile age group was examined for significant changes using a linear model. There was a significant decrease in the proportion of subjects infected with HIV-1 D from 70.3% to 62.4% and a significant increase in subjects infected with HIV-1 A from 16.7% to 23.3% over the eight-year period (p = 0.005). The most marked changes in the proportion of HIV-1 D and A were seen in the younger individuals (<30 years of age, p <0.05). The percent of subjects infected with HIV-1 C and recombinant subtypes did not change significantly. Over this eight-year period the overall viral population in this region evolved toward a less virulent HIV-1 A strain most likely as a consequence of the faster disease progression and lower sexual transmissibility of HIV-1 D as documented above. The significance of these studies is that they provide important epidemiologic, clinical, virologic and immunologic knowledge of HIV infection in developing countries, which can be utilized for monitoring future trends of the epidemic and developing behavioral and biological interventions to prevent further transmission.